H3K36 methylation promotes longevity by enhancing transcriptional fidelity

Payel Sen, Weiwei Dang, Greg Donahue, Junbiao Dai, Jean Dorsey, Xiaohua Cao, Wei Liu, Kajia Cao, Rocco Perry, Jun Yeop Lee, Brian M. Wasko, Daniel T. Carr, Chong He, Brett Robison, John Wagner, Brian D. Gregory, Matt Kaeberlein, Brian K. Kennedy, Jef D. Boeke, Shelley L. Berger

Research output: Contribution to journalArticle

Abstract

Epigenetic mechanisms, including histone post-translational modifications, control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging phenomenon of shortened life span, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a life span screen in Saccharomyces cerevisiae that is designed to identify amino acid residues of histones that regulate yeast replicative aging. Our results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.

Original languageEnglish (US)
Pages (from-to)1362-1376
Number of pages15
JournalGenes and Development
Volume29
Issue number13
DOIs
StatePublished - Jul 1 2015

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Keywords

  • Aging
  • Cryptic transcription
  • Epigenetics
  • H3K36 methylation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., Liu, W., Cao, K., Perry, R., Lee, J. Y., Wasko, B. M., Carr, D. T., He, C., Robison, B., Wagner, J., Gregory, B. D., Kaeberlein, M., Kennedy, B. K., Boeke, J. D., & Berger, S. L. (2015). H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes and Development, 29(13), 1362-1376. https://doi.org/10.1101/gad.263707.115